Histamine has been shown to suppress a variety of immune effector mechanisms in vitro. This property of histamine is H.sub.2 -receptor associated. This effect has been described in the literature as being either directly or indirectly mediated. The direct effect is exerted via the cAMP-mediated suppression of immunocompetent cells. The indirect effect is mediated via the formation of histamine-induced suppressive proteins by suppressor T cells (see, Beer, D. J. et al, Adv. Immunol. 35:209 (1984)).
The concept that histamine may provide a suppressive signal for immune effector cells has also provided the background for other types of studies. One example is the testing of the potential anti-neoplastic effect of cimetidine and other H.sub.2 -receptor blockers, alone or in combination with other anti-neoplastic agents. Results of tests on the effects of these agents on tumor formation which have been conducted in rodents and humans are, however, conflicting. On one hand, the administration of H.sub.2 blockers has been reported to suppress tumor development in rodents and human subjects (see, e.g., Osband, M. E. et al, Lancet 1(8221): 636 (1981). Other studies, on the other hand, report that the same treatment enhances tumor growth and even induces tumors (see, e.g., Barna, B. P. et al, Oncology 40:43 (1983)).
Histamine has also been shown to suppress rather than enhance the growth and occurrence of several types of tumors (see, e.g., Burtin, C. et al, Cancer Lett. 12:195 (1981)). The mechanism for the anti-tumor effects of histamine is not known but has been attributed to H.sup.1 receptor activity (see, e.g., Lespinats, G. et al Br. J. Cancer 50:545 (1984)).
Again, contradictory data exist in this area as well. Histamine, for instance, has been reported to accelerate tumor growth in rodents (Nordlund J. J. et al J. Invest. Dermatol 81:28 (1983)).
Interleukin-2 (IL-2) is a lymphokine which has been ascribed a pivotal role in the expansion of T cells in response to antigen (Smith, K. A. Science 240:1169 (1988)). IL-2 has been shown to exert anti-tumor effects in rodents (see e.g., Lotze, M. T. et al, in "Interleukin 2", ed. K. A. Smith, Academic Press Inc., San Diego, Calif., p. 237 (1988); Rosenberg, S., Ann. Surgery 208:121 (1988)). IL-2 has also been shown to induce partial regression of established tumors in patients with different types of cancer (Rosenberg, S. A. Ann. Surgery 208:121 (1988)). The anti-tumor effect of IL-2 is potentiated when the compound is given together with autologous lymphocytes which have been cultured in vitro with IL-2 and subsequentially been reinfused to the patient (lymphokine-activated killer (LAK) cells) (Rosenberg, S. A., Ann. Surgery 208:121 (1988)). This effect is seen both in rodents and in humans. When used in human anti-cancer trials, IL-2 is usually given at very high doses to human tumor-bearing subjects and has been reported to induce serious side effects, including renal disturbances, anemia, reduced platelet counts, and cardiorespiratory effects. In several of these trials the H.sub.2 -receptor antagonist ranitidine was used to prevent IL-2 induced dyspepsia and nausea (Rosenberg, supra).
NK cells are considered to play an important role in a host's defenses against arising neoplasms as well as against metastases (Hanna, N., Sur. Synth. Pathol. Res. 2:68 (1983); Hanna, N. Biochim. Biophys. Acta 20 780:213 (1985)). Activation of NK cells, in turn, is known to increase a host's resistance against tumor cells (see, e.g., Lotze, M. T. et al., supra).
The following are individual in vitro effects of histamine and IL-2 on the regulation of human NK cells known at the time of this invention.
(1) Histamine augments human NK cell cytotoxicity (NKCC) via H.sub.2 -receptors
Histamine, at concentrations of 10.sup.-4 -10.sup.6 M, has been shown to strongly augment the NKCC of human mononuclear cells (MNC) against K562 leukemic cells. The effect is noted both when the effector cells used are unfractionated MNCs or cells enriched for large granular lymphocytes (LGL) by Percoll density gradient centrifugation. The NK-augmenting response to histamine is also mimicked by the H.sub.2 -receptor agonist dimaprit with similar potency and efficacy. Two structural analogs to dimaprit, nor-dimaprit and N-methyl-dimaprit, both lacking activities as H.sub.2 -receptors, proved to be ineffective under the same test conditions. The NK-augmenting effects of histamine and dimaprit were shown to be completely antagonized by the H.sub.2 -receptor antagonists ranitidine and cimetidine. The NK-augmenting effect of histamine was shown to require the presence of monocytes. In the absence of monocytes, histamine had no effect or weakly suppressed NKCC at the histamine concentrations mentioned. (Hellstrand, K., et al, J. Immunol. 137:656 (1986)).
(2) Histamine suppresses NK cell activity via T cells
In contrast to the above-mentioned NK cell activation induced by histamine in the presence of monocytes, histamine has been reported to suppress NKCC against K562 cells in the presence of T lymphocytes. Thus, in vitro treatment of human T cells with histamine (10.sup.-3 -10.sup.-8 M) induces the production of a soluble factor, histamine-induced soluble suppressor factor (HISSF) that inhibited NK cell cytotoxicity. NK cells alone do not produce HISSF. Production of HISSF induced by histamine is blocked by cimetidine but not by an H.sub.1 -receptor antagonist. The inhibition of NK cell cytotoxicity by HISSF is reduced by the addition of IL-2 (6.4-64 U/ml) or interferon-.alpha. (500 U/ml) (Nair, M.P.N. et al., J. Immunol. 136:2456 (1986)). Further, it has been shown that the T-cell mediated suppressive effect of histamine on NK-cell related cytotoxicity is more pronounced in the presence of IL-2 (Welt, S. et al., Proc. Annu. Meet. Am. Soc. Clin. Oncol. 7:A632 (1988)).
(3) Enhancement Of NK Cell Cytotoxicity by IL-2.
IL-2 rapidly and effectively augments the cytotoxicity of isolated human NK cells in vitro over a broad range of concentrations. The effect has been described both with natural and recombinant forms of IL-2 (Dempsey, R. A., et al., J. Immunol. 129:2504 (1982); Phillips, J. H., et al., J. Exp. Med. 170:291 (1989)). The NK-augmenting effect of IL-2 is related to a cellular IL-2 receptor (IL-2R), p 75 (IL-2R.alpha.) which is expressed on human NK cells (Siegel, J. P. Science 238:75 (1987); Phillips, J. H., et al., supra). The effect of IL-2 on NK cells is of relevance for the anti-tumor effect induced by this compound since depletion of NK cells from mice was reported eliminate anti-tumor effects induced by IL-2 treatment (Lotze, M. T., et al., supra).
In view of the high incidence of cancer in the human population and the at best partial success obtained at present with the different therapies in existence, there is still a need for further improved methods of treating tumors in humans.